Bacteria-derived metabolite, methylglyoxal, modulates the longevity of C. elegans through TORC2/SGK-1/DAF-16 signaling

Abstract

<jats:p>Gut microbes play diverse roles in modulating host fitness, including longevity; however, the molecular mechanisms underlying their mediation of longevity remain poorly understood. We performed genome-wide screens using 3,792 <jats:italic>Escherichia coli</jats:italic> mutants and identified 44 <jats:italic>E. coli</jats:italic> mutants that modulated <jats:italic>Caenorhabditis elegans</jats:italic> longevity. Three of these mutants modulated <jats:italic>C. elegans</jats:italic> longevity via the bacterial metabolite methylglyoxal (MG). Importantly, we found that low MG-producing <jats:italic>E. coli</jats:italic> mutants, <jats:italic>Δhns E. coli</jats:italic>, extended the lifespan of <jats:italic>C. elegans</jats:italic> through activation of the DAF-16/FOXO family transcription factor and the mitochondrial unfolded protein response (UPR<jats:sup>mt</jats:sup>). Interestingly, the lifespan modulation by <jats:italic>Δhns</jats:italic> did not require insulin/insulin-like growth factor 1 signaling (IIS) but did require TORC2/SGK-1 signaling. Transcriptome analysis revealed that <jats:italic>Δhns E. coli</jats:italic> activated novel class 3 DAF-16 target genes that were distinct from those regulated by IIS. Taken together, our data suggest that bacteria-derived MG modulates host longevity through regulation of the host signaling pathways rather than through nonspecific damage on biomolecules known as advanced glycation end products. Finally, we demonstrate that MG enhances the phosphorylation of hSGK1 and accelerates cellular senescence in human dermal fibroblasts, suggesting the conserved role of MG in controlling longevity across species. Together, our studies demonstrate that bacteria-derived MG is a novel therapeutic target for aging and aging-associated pathophysiology.</jats:p>

The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

“…mTOR, a relatively large (259 kDa) and highly conserved serine/threonine protein kinase regulated mainly by the PI3K/Akt signaling pathway [144], plays a central role in the aging process [121,122,145]. Research in the nematode C. elegans and the fruit fly Drosophila melanogaster was the first to show that mTOR regulates lifespan [146,147].…”

Prohibitin depletion extends lifespan of a TORC2/SGK‐1 mutant through autophagy and the mitochondrial UPR

“…Many longevity experiments have been performed using different rict ‐ 1 and sgk ‐ 1 alleles and RNAi under different conditions. What seems consistent, so far, is that in the presence of FUdR, deficient TORC2/SGK‐1 signalling shortens lifespan regardless of the food source when grown at 20°C, while at 25°C it shortens lifespan in OP50 but it extends lifespan in K12‐type bacterial strains (HT115 and BW25113; Alam et al, 2010; Chen et al, 2013; Mizunuma et al, 2014; Shin et al, 2020; Soukas et al, 2009; Xiao et al, 2013; Zhou et al, 2019). However, in the absence of FUdR, TORC2/SGK‐1 deficiency consistently extends lifespan regardless of food source and temperature (Evans et al, 2008; Gatsi et al, 2014; Hertweck et al, 2004; Mizunuma et al, 2014; Rahman et al, 2010; Shin et al, 2020; Soukas et al, 2009).…”

“…Thus, it is possible that additional mitochondrial stress could revert the ageing phenotype and other physiological responses of TORC2/SGK-1 animals, which already have compromised mitochondrial function (Aspernig et al, 2019;Gatsi et al, 2014;Zhou et al, 2019). In agreement, FUdR partially suppresses the extended lifespan of mitochondrial mutants (Shin et al, 2020). Thus, it is possible that mild mitochondrial dysfunction contributes to the extended lifespan of sgk-1 mutants.…”

Potential Roles of Exercise-Induced Plasma Metabolites Linking Exercise to Health Benefits

“…Recently, it has been observed that physical exercise modulates gut microbiota in both humans and animals ( Clarke et al, 2014 ; Barton et al, 2018 ). Of note, bacteria-derived metabolites play critical roles in the modulation of aging and longevity in the host organism ( Smith et al, 2017 ; Shin et al, 2020 ). Thus, microbiota-derived metabolites could be important mediators of the benefits of exercise.…”